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Friday, 26 June 2015

This Kat blogged last year about the masterful and erudite judgment of Mr Justice Arnold in the case of Actavis v Lilly (judgment on BAILII here), concerning pemetrexed. A judgment that was Arnoldian even by Arnoldian standards was necessitated by the fact that the case required consideration of the law in four different jurisdictions. Actavis appeared to have won comprehensively - their pemetrexed dipotassium product did not infringe Lilly's patent directed to pemetrexed disodium either under direct infringement, or under indirect infringement; the law applicable to whether Actavis was entitled to a Declaration of Non-Infringement was English law, under which Actavis prevailed; but even if French, Italian and Spanish law is the applicable law respectively, Actavis were entitled to a DNI in respect of the French, Italian and Spanish designations of the Patent. So what could possibly go wrong for Actavis? Well, quite a lot, as it turns out. In the admirably brief Court of Appeal decision just out -Actavis UK Ltd & Others v Eli Lilly & Company [2015] EWCA Civ 555 (25 June 2015) , Lord Justice Floyd (Lord Justice Kitchin and Lord Justice Longmore concurring) disagreed with Arnold J on two main issues - one on which nothing turns in the end (although it has important wider significance), and one which has the result that this case seems set to run and run.

The claim
But let's recap a bit. The main claim at issue is a Swiss form claim, and although this is significant for the present case, much less turns on it than in the other saga ongoing at the moment of Warner Lambert v Actavis (latest instalment here). The claim was as follows:

Use of pemetrexed disodium in the manufacture of a medicament for use in combination therapy for inhibiting tumor growth in mammals wherein said medicament is to be administered in combination with vitamin B12 or a pharmaceutical derivative thereof, said pharmaceutical derivative of vitamin B12 being hydroxocobalamin, cyano-10-chlorocobalamin, aquocobalamin perchlorate, aquo-10-chlorocobalamin perchlorate, azidocobalamin, chlorocobalamin or cobalamin.

The main issue was whether this could be infringed by a different pemetrexed salt such as pemetrexed dipotassium, or by the free acid, notwithstanding that the claim said "pemetrexed disodium".

Issue 1 - Prosecution history as an aid to construction

In the first instance judgment, Arnold J drew significant support from the prosecution history of the patent when considering how broadly the claim could be construed. Floyd LJ has roundly rejected Arnold J's reasoning, stating:

58.The difficulty I feel with endorsing this reasoning is as follows. Firstly it assumes that the skilled reader will always read the prosecution history. I do not see why this should be so, given the limited value which, at least before the judgment in this case, it was generally recognised to have. Secondly, and more importantly, it suggests that the story told by the prosecution history of how the claims came to be drafted as they were will assist the court in preventing abuse of the system. To my mind this will be a very rare case indeed. Unless the acceptance of a restriction in a claim is to operate as some kind of estoppel against the patentee arguing for wider claims (a proposition for which neither side contended and which Jacob J rejected, at least on the basis of domestic estoppel, in Bristol Myers), there will always remain an issue as to whether the applicant needed to accept the restriction notwithstanding that he did so. In those circumstances, the light which the prosecution history sheds on the ultimate question of construction is likely to be extremely limited.

59.I therefore do not regard it as useful to go to the prosecution history in order to discover that the patentee accepted a restriction to his claim against an objection of lack of support in the specification. It is always open to a party attacking the patent to argue that the claims as sought to be construed by the patentee lack support in the specification: see for exampleAmerican Home Products v Novartis [2001] RPC 8 at [31]. What purpose does it serve to illustrate this point by showing that the patentee was faced with an official objection to that effect and amended his claims in the light of it? It is still open to the patentee to say that he need not have done so, and the apparent concession he made in prosecution was wrongly made. If it is not open to the patentee so to contend, then the prosecution history is indeed creating a form of estoppel.

60.In any event, patent offices are usually concerned with patentability, not scope of protection. If an applicant were to conclude every letter by saying that he did not accept that by accepting this or that limitation he was necessarily restricting the scope of protection, no inference could be drawn from his conduct in accepting it. I would be reluctant to put the patent attorneys' profession to this unnecessary trouble.

He also quoted a lovely passage from Lord Hoffmann's speech in Kirin-Amgen:

The courts of the United Kingdom, the Netherlands and Germany certainly discourage, if they do not actually prohibit, use of the patent office file in aid of construction. There are good reasons: the meaning of the patent should not change according to whether or not the person skilled in the art has access to the file and in any case life is too short for the limited assistance which it can provide.

So the interesting prospect that prosecution history might become important in UK patent litigation has been firmly quashed by the Court of Appeal. Actually, Mr Justice Arnold had himself moved away from the idea already - he distinguished his decision in the later case of Idenix Pharmaceutical, Inc v Gilead Sciences, Inc (reported by IPKat here) in which he declined to construe a claim narrowly on the basis of the prosecution history.

This did not however have any effect on the outcome - Floyd LJ otherwise endorsed Arnold J's application of the Protocol questions to likewise find that there was no direct infringement of the claim by pemetrexed dipotassium. This Kat would have wept if the outcome had been otherwise, and indeed in the meantime the decision of the Landgericht Düsseldorf finding infringement had been overturned by the Oberlandesgericht Düsseldorf (referring, ironically, to Arnold J's decision).

Issue 2 - indirect infringement and the issue of solutions

Where Actavis came unstuck was in the matter of indirect infringement. The issue is that the pemetrexed (whether free acid or any of its salts) is generally reconstituted in saline - that would be sodium chloride solution - before administration by injection. Floyd LJ considered that the resulting solution could certainly be regarded as "pemetrexed disodium", even if the solid going in to make it was another salt or the free acid. On that basis, supply of, for example, pemetrexed dipotassium to be made up in this way, would be "supply ... of the means, relating to an essential element of the invention", and thus indirect infringement under Section 60(2) of the Patents Act.

Arnold J had considered that the essential element had to be the sodium salt, and that the potassium salt could not be it. Floyd LJ deduced from the wording of the first instance decision that it had overlooked that the solution could be "pemetrexed disodium" even if the salt going into it was not, and thus had (wrongly according to Court of Appeal) assumed that the pemetrexed disodium has to be in the solid form.

So Lilly was saved by the fact that the compound was to be made up in saline solution, and this fact was critical to the finding of indirect infringement by the Court of Appeal. On little facts do big cases turn.

Outcome and next steps
As a result of the finding of indirect infringement, even if not direct infringement, Floyd LJ ruled that Actavis were not entitled to a declaration (so all the issues relating to the non-UK designations of the patent became irrelevant, although in fact Floyd LJ would have agreed with Arnold J on these). Despite a flurry of post-appeal submissions, which delayed the handing down of the decision, he declined to issue a declaration in respect of direct infringement only, or a declaration that specified that Actavis would infringe if the product was to be made up (more specifically, if Actavis knows, or it is obvious in the circumstances, that the product is suitable and intended for being reconstituted) in saline in appropriate amounts to equate to a disodium salt. He declined even more strongly to issue a declaration that specified that Actavis would infringe if and only if the product was to be made up in saline in appropriate amounts to equate to a disodium salt. Any such declaration was open to being misconstrued.

However, in the meantime, Actavis had come up with a plan to specify that their product should be made up in dextrose solution rather than saline solution. They contended as a further point in their post-appeal submissions that this would require remittal to the first instance to consider whether this proposal would be sufficient to circumvent the claim, since it was possible that, notwithstanding their directions, a user might use saline instead.

On this point, the Court of Appeal granted remittal, so the case is off back to the Patents Court. So there will be more volumes of the saga to come, it seems.

7 comments:

From a stay at Kingston Hospital some years ago, I am aware that there exist products analogous to "saline", but based on potassium chloride. Would the use of one of these products be a way of avoiding infringement?

Applying the Court of Appeal's approach, it seems likely that use of any medically-acceptable and non-sodium-containing carrier would avoid infringement. We have written a commentary on this decision (and the ConvaTec decision) on http://patlit.blogspot.co.uk/2015/06/precisely-delineated-claims-and.html

I must say that I am not convinced that this decision is based on a correct construction of the Swiss form of claim. Allowing that the "manufacture of a medicament" may comprise a step of the treating practitioner making up a solution of a commercial compound for injection would appear to circumvent the prohibition on patenting methods of medical treatment that the Swiss form itself was designed to work around. After all, on the court's construction the practitioner is the direct infringer which, as a matter of policy, is precisely the situation the prohibition is intended to avoid.

If Lilly had wanted to claim the "use of pemetrexed, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament..." then it should have done so. The court's job is not to rewrite the patentee's claims to cover that which, with the benefit of hindsight, it should have claimed in the first place!

To xxxxxx - the solutions that you link to contain more sodium chloride than potassium chloride. I would emphasise again the issue of the quantity. According to Wikipedia the lethal LD50 by injection is 30mg/kg; I suspect that if sodium chloride is also present the toxicity may be lower. But I also repeat that I am not a medical expert.

To Brian - indeed if saline was avoided entirely, such as the dextrose based proposal, then infringement would be avoided. But as Actavis has already highlighted, there is the issue of what happens if users use saline even though the instructions say dextrose solution.

To Mark - yes an appeal to the Supreme Court is possible with permission. I think there is force in both the points you raise, and if I may dare to suggest an opinion I would venture to agree with you. I called Arnold J's judgment masterful and erudite because I think he was probably correct.

"A second question is whether the skilled person would understand that the ratio of sodium ions to pemetrexed ions in the solid state (i.e. 2:1) should be maintained in the solution. I am fully prepared to accept that the ratio must reach the threshold of 2:1: anything less would not meet the description “disodium”. However I cannot see why the presence of more sodium ions, i.e. in excess of the 2:1 ratio should be regarded as material."

As a chemist, I can certainly see a reason why a solution prepared a different way (e.g. by dissolving pemetrexed dipotassium in saline) might not be described as the "disodium" salt. That is, unless there are so many sodium ions in solution as to totally swamp the potassium ions (e.g. as one might try to achieve if attempting a potassium to sodium cation metathesis), then the chemist would be more likely (if being suitably loose with terminology) to describe the solution as being a mixed potassium / sodium salt.

In any event, should the court not have heard expert evidence on this precise point before reaching a decision? The experts might not agree with the conclusion in para 79 that the presence of other counter-ions does not make a difference.

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